Liposomes are composed of phospholipids that constitute cell membranes of organisms, they have high biocompatibility, and they can deliver drugs and active ingredients while protecting them from degrading enzymes in vivo. Accordingly, liposomes have drawn attention as useful tools for drug delivery systems. In recent years, liposomes modified with polyethylene glycol (PEG) that improves retentivity in the blood and liposomes comprising, as constitutional lipids, hydrogenated phosphatidylcholine free of unsaturated bonds that enhances stability in the blood and strength and cholesterols that elevate the phase transition temperature of the membrane have been developed and generally used.
Meanwhile, RNAi molecules that induce RNA interference (hereafter referred to as “RNAi”) have drawn attention as useful tools for tumor treatment and other purposes, and a wide variety of RNAi molecules that are capable of tumor growth inhibition have been developed. In addition, a method of using complexes composed of RNAi molecules and liposomes (i.e., lipoplexes) to deliver RNAi molecules as active ingredients to tumor cells has been developed (Qixin Leng et al., Drug Future, September 2009; 34 (9): 721; Sherry Y., Wu et al., The AAPS Journal, Vol. 11, No. 4, December 2009; and B. Ozpolat et al., Journal of Internal Medicine 267; 44-53, 2009).
In the past, the present inventors developed RNAi molecules targeting thymidylate synthases (hereafter referred to as “TS”), which is involved with DNA synthesis (WO 2010/113844). They reported that delivery of such RNAi molecules to the tumors via intravenous administration with the use of PEG-modified liposomes containing cholesterols at a given concentration would make it possible to inhibit the growth of tumors showing TS expression. They also reported that the use of such liposomes in combination with chemotherapeutic agents would result in tumor tropism improvement as well as the improvement of antitumor effects of RNAi molecules to a significant extent (WO 2012/161196).
However, development of a means that makes it possible to more efficiently introduce RNAi molecules capable of tumor growth inhibition into tumor cells has been awaited in the art.